The present invention relates to preparations of zinc compounds for use in the treatment and/or prophylaxis of the common cold.
Zinc and its compounds have long been recognized as possessing certain therapeutic functions. Particularly well recognized are benefits as astringents and wound healing agents. The latter use tends to be restricted to zinc chloride and zinc sulphate, zinc chloride being of use for application to foul-smelling wounds and ulcers, while zinc sulphate is given internally to promote healing.
Zinc sulphate has also proven beneficial in the treatment of acrodermatitis enteropathica and, in common with zinc acetate, is used in eye drops, optionally in combination with adrenaline or boric acid (no longer medically recommended), to relieve chronic inflammation of the cornea in conjunctivitis. Together with zinc chloride, zinc sulphate is also used as an astringent mouth wash, and was formerly used as a reflex emetic, owing to its irritant and adverse effects on the gastrointestinal mucosae (of Merck Index, entry 9966).
Zinc compounds have also been used, with varying degrees of success, in the treatment of acne, aphthous ulcers, coeliac disease, cystic fibrosis, senile dementia, furunculosis, gastric ulcers, hyperthyroidism, leg ulcers, porphyria, rheumatoid arthritis, sickle-cell anaemia and ulcerative colitis.
Approximately 40% of common colds are caused by rhinovirus infections. The precise mechanism of action is not known, although zinc has been shown to inhibit virion maturation by blocking cleavage of the large polypeptide which is the primary transcription product of the vital genome. This effect may be caused by zinc acting as a protease inhibitor or by binding to and stabilizing regions of the precursor polypeptides. The latter possibility is supported by the observation that the polypeptides accumulating in the infected cell, in the presence of zinc, are primarily those containing coat protein sequences. Zinc has been shown to bind readily to purified rhinovirus, preventing normal crystallization.
In addition, rhinoviruses passaged in the presence of zinc (zinc resistant mutants) have been shown to display altered antigens. This suggests that zinc may affect the in vitro pathogenicity of the virus by making virions more susceptible to antibody attack as well as reducing the amounts of transmissible virus released.
Of two reports on the effects of zinc (see below), administered orally, on rhinovirus infections, one involved infecting healthy volunteers with purified virus, while the other involved subjects with naturally acquired infections. Both examined the effects of orally administered zinc gluconate (lozenges with 23 mg Zn) on symptom severity. Significant effects on duration of symptoms, overall symptom severity and the amount of nasal secretion were detected.
Accordingly, investigation of zinc compounds has centered upon their possible use to inhibit or cure the common cold. For example, Eby, et al. (Antimicrobial Agents and Chemotherapy [1984], 25, [1], pp 20-24) disclose the use of zinc gluconate lozenges in the treatment of the common cold. Their study indicated that, after 7 days, 86% of zinc-treated subjects were asymptomatic, compared with only 46% of placebo-treated subjects. However, the observers noted "objectionable taste and mouth irritation" in the patients.
With one exception, attempts to duplicate Eby's results have been uniformly negative. Eby's original results were questioned, given that, as noted above, zinc ions taste metallic and cause a sore mouth and nausea in the patient. In addition, the Merck Index (10th Edition) notes zinc sulphate as being irritating to both skin and mucous membranes, and states that a solution of zinc sulphate has a pH of 4.5. For a review of results obtained with zinc gluconate, see Antimicrobial Agents and Chemotherapy (1988), 32, pp. 605-7.
In U.S. Pat. No. 4,503,070, Eby discloses the use of nasal sprays of zinc solutions to treat the common cold. However, not only is such use unsupported by the description, but the concentrations to which such sprays are limited are of an order of magnitude so large as to cause substantial discomfort to the patient. Prior art is also described therein comprising the use of suspensions of zinc borate. Such suspensions provide high quantities of zinc but are essentially ineffective and, in addition, the particles may block the alveoli of the lungs, which can ultimately give rise to a condition similar to emphysema.
In a later unpublished paper, the conclusions of which were, however, published in a letter to the Lancet, Eby et al. established that a zinc gluconate nasal spray (10 mM) was only marginally effective, and was not worth following up. Also, DE 3431727 A1, filed in 1984, discloses a nasal spray comprising zinc gluconate in a 2% solution. No results are provided, and the applicant failed to continue with the application.
In two other papers in Antimicrobial Agents and Chemotherapy ([1987], 31, 1183-7 and 1263-5), it was established that neither zinc gluconate nor zinc acetate provided a therapeutically useful treatment of rhinovirus colds.